Neonatal hypofunction of NMDARs during early postnatal development
impairs the induction of long-term potentiation in the LPP – DG
synapse.
Granule cells undergo LTP through multiple stimulation patterns that
mimic PP activity impinging on the DG. These stimulation protocols are
physiologically and behaviorally relevant (Lopez-Rojas et al., 2016);
among them, theta-burst stimulation (TBS) has been successfully used to
induce stable LTP at the MPP and LPP synapses (Lopez-Rojas et al., 2016;
Vyleta and Snyder, 2021). Therefore, we applied TBS to the LPP to test
the effects of neonatal MK-801 on LTP induction. A stable baseline of
LPP fEPSP slope was recorded for 20 min prior to TBS [3 episodes
repeated at 10 s; each episode included 5 pulses delivered at 100 Hz and
repeated 10 times at 5 Hz (Larson and Munkácsy, 2015)]. Recording
continued for 90 min and was followed by perfusion of L-AP4 (20 µM). In
the control condition, TBS triggered a marked post-tetanic potentiation
(LPP PTP), followed by long-lasting LPP fEPSP slope potentiation (fEPSP
at PTP: 213.4 ± 23.13% of baseline; fEPSP 90 min post-TBS: 144.6
±13.28% of baseline; fEPSP in presence of L-AP4: 23.18 ± 3.82% of
baseline; n = 7 slices / 6 animals, traces and black bars in
Figure 6a-b). On the other hand, on the MK-801-treated slices, TBS
caused a strong PTP but did not induce a sustained increase in the slope
of the fEPSP, as illustrated in the green traces and green symbols in
Figure 6a-b (fEPSP at PTP: 239.9 ± 18.28% of baseline; fEPSP 90 min
post-TBS: 105.5 ± 10.9% of baseline, Mann-Whitney test, P< 0.05 vs. control; fEPSP in presence of L-AP4: 28.01 ± 4.33%
of baseline; n = 7 slices / 7 animals). Interestingly, by
adjusting a best-fit single exponential decay function, we found that
decay of PTP (tau, 𝜏) is faster in MK-801-treated slices than control
slices, suggesting short-term plasticity dysregulation (𝜏 in control:
114 ± 23.38 s; 𝜏 in MK-801: 47.03 ± 5.88 s, Mann-Whitney test, P< 0.05: inset in Figure 6b).
The bar graphs in Figure 6c summarize the mean PTP, potentiation, and
sensitivity to L-AP4, while the symbols represent the individual
experiments for the control condition and MK-801-treated slices. The
heatmaps in Figure 6d contrast the magnitude of the potentiation
obtained in each slice, and the cumulative probability graph in Figure
6e shows the overall potentiation for control slices (black symbols) vs.
MK-801-treated slices (green symbols). Together, these experiments show
that the potentiation of the LPP fEPSP is sensitive to the transient
hypofunction of NMDARs during early postnatal development.